A variety of vessels and methods have been developed over the years to carry out chemical, biochemical and/or biological processing. Stainless steel fermentation vessels of several hundreds of thousands liters are not uncommon for the growth of microorganisms that produce enzymes or secondary metabolites. The methods include batch, fed-batch, continuous or semi-continuous perfusion. Gradually, more challenging cultures such as mammalian, insect or plant cells have been adapted for growth in fermentation vessels using highly specialized media. Although the design of these vessels differs in detail, they have several common features. The cells are kept in suspension by rotating stirring blades placed vertical in the vessel, and gas exchange is facilitated by injection of air, oxygen or carbon dioxide.
There are several drawbacks to this design: the shearing forces that are introduced through the stirring blades and the cavitation of miniscule air bubbles is detrimental to more sensitive cell types or organisms. Also, these vessels have to be rigorously cleaned between production runs to prevent cross-contamination, which is time consuming and needs to be validated for individual cultures. Furthermore, the use of stirred fermentors requires highly trained operators. The cost price for stirred fermentors is high across the whole size range and therefore they are used repeatedly over long periods of time, thus increasing infection risks as a result of mechanical failures. Perhaps most significantly, the optimization of culture conditions for stirred fermentors in a small scale cannot be transferred in a linear way to commercial scale production. For example, the fluid dynamics, aeration, foaming and cell growth properties change with an order of magnitude when the scale increases. In addition, for more delicate cell types or organisms, a large scale stirred fermentation vessel is not a viable device, even when more subtle stirring techniques such as airlift fermentors are used.
These drawbacks have led to the development of disposable fermentors. Examples of such disposable fermentors are systems based on wave agitation. See, e.g., U.S. Pat. No. 6,544,788; PCT Publication WO 00/66706. This type of fermentor may be used to culture relatively sensitive cells such as CHO cells (e.g., Pierce, Bioprocessing J. 3: 51-56 (2004)), hybridoma cells (e.g., Ling et al., Biotech. Prog., 19: 158-162 (2003)), insect cells (e.g., Weber et al., Cytotech. 38: 77-85 (2002)) and anchorage-dependent cells (e.g., Singh, Cytotech. 30: 149-158 (1999)) in a single disposable container. Such disposable units are relatively cheap, decrease the risk of infection because of their single use and require no internal stirring parts as the rocking platform induces wave-like forms in the liquid phase to facilitate gas exchange. However, this principle cannot be expanded to the size of hundreds of thousands of liters (such as the industrial fermentors) but are currently available from 1 liter to 500 liters (total volume of the disposable bag, available from Wave Biotechnology AG, Switzerland; Wave Biotech Inc., USA). Moreover, the hydrodynamics for each size of these disposable bags will differ as a result of differences in depth and height. Therefore, the use of these disposable bags requires optimization and re-validation of each step in an up-scaling process.
Although bioreactor systems and related processes are known, improvements to such systems and processes would be useful in the preparation of a variety of products produced from a biological source.